The present invention relates to imidazolidinone derivatives, their synthesis, and their use as xcex1v integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors xcex1vxcex23, xcex1vxcex25, and xcex1v integrin receptors associated with other xcex2-subunits, and are useful for inhibiting bone resorption, treating and/or preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
It is believed that a wide variety of disease states and conditions can be mediated by acting on integrin receptors and that integrin receptor antagonists represent a useful class of drugs. Integrin receptors are heterodimeric transmembrane receptors through which cells attach and communicate with extracellular matrices and other cells. (See S. B. Rodan and G. A. Rodan, xe2x80x9cIntegrin Function In Osteoclasts,xe2x80x9d Journal of Endocrinology, 154: S47-S56 (1997), which is incorporated by reference herein in its entirety).
In one aspect of the present invention, the compounds herein are useful for inhibiting bone resorption. Bone resorption is mediated by the action of cells known as osteoclasts. Osteoclasts are large multinucleated cells of up to about 400 mm in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. Osteoclasts are actively motile cells that migrate along the surface of bone, and can bind to bone, secrete necessary acids and proteases, thereby causing the actual resorption of mineralized tissue from the bone. More specifically, osteoclasts are believed to exist in at least two physiological states, namely, the secretory state and the migratory or motile state. In the secretory state, osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone. The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the migratory or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption until they again attach to bone.
Integrins are involved in osteoclast attachment, activation and migration. The most abundant integrin on osteoclasts, e.g., on rat, chicken, mouse and human osteoclasts, is an integrin receptor known as xcex1vxcex23, which is thought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to xcex1vxcex23 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that xcex1vxcex23 ligands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals.
The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget""s disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site; for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
In the United States, there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis. In addition, there are about 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.
Additionally, xcex1vxcex23 ligands have been found to be useful in treating and/or inhibiting restenosis (i.e. recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis (i.e. formation of new blood vessels), and inhibiting viral disease. Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus, inhibition of angiogenesis can cause tumor regression in animal models (See Harrison""s Principles of Internal Medicine, 12th ed., 1991, which is incorporated by reference herein in its entirety). Therefore, xcex1vxcex23 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See, e.g., Brooks et al., Cell, 79:1157-1164 (1994), which is incorporated by reference herein in its entirety).
Evidence has also been presented suggesting that angiogenesis is a central factor in the initiation and persistence of arthritic disease, and that the vascular integrin xcex1vxcex23 may be a preferred target in inflammatory arthritis. Therefore, xcex1vxcex23 antagonists which inhibit angiogenesis may represent a novel therapeutic approach to the treatment of arthritic disease, such as rheumatoid arthritis (see C. M. Storgard, et al., xe2x80x9cDecreased angiogenesis and arthritic disease in rabbits treated with an xcex1vxcex23 antagonist,xe2x80x9d J. Clin. Invest., 103: 47-54 (1999), which is incorporated by reference herein in its entirety).
Moreover, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor, xcex1vxcex25. A monoclonal antibody for xcex1vxcex25 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model (See M. C. Friedlander, et al., Science 270: 1500-1502 (1995), which is incorporated by reference herein in its entirety). Thus, compounds that antagonize xcex1vxcex25 are useful for treating and preventing macular degeneration, diabetic retinopathy, cancer, and metastatic tumor growth.
Additionally, compounds of the instant invention can inhibit angiogenesis and inflammation by acting as antagonists of xcex1v integrin receptors associated with other xcex2 subunits, such as xcex1vxcex26 and xcex1vxcex28 (See, for example, Melpo Christofidou-Solomidou, et al., xe2x80x9cExpression and Function of Endothelial Cell xcex1v Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin/SCID Mice Chimeras,xe2x80x9d American Journal of Pathology, 151: 975-83 (1997) and Xiao-Zhu Huang, et al., xe2x80x9cInactivation of the Integrin xcex26 Subunit Gene Reveals a Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin,xe2x80x9d Journal of Cell Biology, 133: 921-28 (1996), which are incorporated by reference herein in their entirety).
In addition, certain compounds of this invention antagonize both the xcex1vxcex23 and xcex1vxcex25 receptors. These compounds, referred to as xe2x80x9cdual xcex1vxcex23/xcex1vxcex25 antagonists,xe2x80x9d are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
Peptidyl as well as peptidomimetic antagonists of the xcex1vxcex23 integrin receptor have been described both in the scientific and patent literature. For example, reference is made to W. J. Hoekstra and B. L. Poulter, Curr. Med. Chem. 5: 195-204 (1998) and references cited therein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO 98/08840; WO 98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO 98/30542; WO 99/15506; WO 99/15507; WO 00/03973; EP 853084; EP 854140; EP 854145; U.S. Pat. Nos. 5,204,350; 5,217,994; 5,639,754; 5,741,796; 5,780,426; 5,929,120; 5,952,341; 6,017,925; and 6,048,861. Evidence of the ability of xcex1vxcex23 integrin receptor antagonists to prevent bone resorption in vitro and in vivo has been presented (see V. W. Engleman et al., xe2x80x9cA Peptidomimetic Antagonist of the xcex1vxcex23 Integrin Inhibits Bone Resorption In Vitro and Prevents Osteoporosis In Vivo,xe2x80x9d J. Clin. Invest. 99: 2284-2292 (1997); S. B. Rodan et al., xe2x80x9cA High Affinity Non-Peptide xcex1vxcex23 Ligand Inhibits Osteoclast Activity In Vitro and In Vivo,xe2x80x9d J. Bone Miner. Res. 11: S289 (1996); J. F. Gourvest et al., xe2x80x9cPrevention of OVX-Induced Bone Loss With a Non-peptidic Ligand of the xcex1vxcex23 Vitronectin Receptor,xe2x80x9d Bone 23: S612 (1998); M. W. Lark et al., xe2x80x9cAn Orally Active Vitronectin Receptor xcex1vxcex23 Antagonist Prevents Bone Resorption In Vitro and In Vivo in the Ovariectomized Rat,xe2x80x9d Bone 23: S219 (1998)).
The xcex1vxcex23 integrin receptor recognizes the Arg-Gly-Asp (RGD) tripeptide sequence in its cognate matrix and cell surface glycoproteins (see J. Samanen, et al., xe2x80x9cVascular Indications for Integrin xcex1v Antagonists,xe2x80x9d Curr. Pharmaceut. Design 3: 545-584 (1997)). A benzazepine nucleus has been employed among others by Genentech and SmithKline Beecham as a conformationally constrained Gly-Asp mimetic to elaborate nonpeptide xcex1vxcex23 integrin receptor antagonists substituted at the N-terminus with heterocyclic arginine mimetics (see R. M. Keenan et al., xe2x80x9cDiscovery of Potent Nonpeptide Vitronectin Receptor (xcex1vxcex23) Antagonists,xe2x80x9d J. Med. Chem. 40: 2289-2292 (1997); R. M. Keenan et al., xe2x80x9cBenzimidazole Derivatives As Arginine Mimetics in 1,4-Benzodiazepine Nonpeptide Vitronectin Receptor (xcex1vxcex23) Antagonists,xe2x80x9d Bioorg. Med. Chem. Lett. 8: 3165-3170 (1998); and R. M. Keenan et al., xe2x80x9cDiscovery of an Imidazopyridine-Containing 1,4-Benzodiazepine Nonpeptide Vitronectin Receptor (xcex1vxcex23) Antagonist With Efficacy in a Restenosis Model,xe2x80x9d Bioorg. Med. Chem. Lett. 8: 3171-3176 (1998). Patents assigned to SmithKline Beecham that disclose such benzazepine, as well as related benzodiazepine and benzocycloheptene, xcex1vxcex23 integrin receptor antagonists include WO 96/00574, WO 96/00730, WO 96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO 97/24124, WO 98/14192, WO 98/15278, WO 99/05107, WO 99/06049, WO 99/15170, WO 99/15178, and WO 99/15506, and to Genentech include WO 97/34865. The dibenzocycloheptene, as well as dibenzoxazepine, nucleus has also been employed as a Gly-Asp mimetic to afford xcex1vxcex23 antagonists (see WO 97/01540, WO 98/30542, WO 99/11626, WO 99/15508, U.S. Pat. Nos. 6,008,213, and 6,069,158, all assigned to SmithKline Beecham).
Other integrin receptor antagonists incorporating backbone conformational ring constraints have been described in the patent literature. Published patent applications or issued patents disclosing antagonists having a phenyl constraint include WO 98/00395, WO 99/32457, WO 99/37621, WO 99/44994, WO 99/45927,WO 99/52872, WO 99/52879, WO 99/52896, WO 00/06169, EP 0 820,988, EP 0 820,991, U.S. Pat. Nos. 5,741,796; 5,773,644; 5,773,646; 5,843,906; 5,852,210; 5,929,120; 5,952,381; 6,028,223; and 6,040,311. Published patent applications or issued patents disclosing antagonists having a monocyclic ring constraint include WO 99/26945, WO 99/30709, WO 99/30713, WO 99/31099, WO 99/59992, WO 00/00486, WO 00/09503, EP 0 796,855, EP 0 928,790, EP 0 928,793, U.S. Pat. Nos. 5,710,159; 5,723,480; 5,981,546; 6,017,926; and 6,066,648. Published patent applications or issued patents disclosing antagonists having a bicyclic ring constraint include WO 98/23608, WO 98/35949, WO 99/33798, EP 0 853,084, U.S. Pat. Nos. 5,760,028; 5,919,792; and 5,925,655.
Reference is also made to the following reviews for additional scientific and patent literature that concern alpha v integrin antagonists: M. E. Duggan, et al., xe2x80x9cLigands to the integrin receptor xcex1vxcex23, Exp. Opin. Ther. Patents, 10: 1367-1383 (2000); M. Gowen, et al., xe2x80x9cEmerging therapies for osteoporosis,xe2x80x9d Emerging Drugs, 5: 1-43 (2000); J. S. Kerr, et al., xe2x80x9cSmall molecule xcex1v integrin antagonists: novel anticancer agents,xe2x80x9d Exp. Opin. Invest. Drugs, 9: 1271-1291 (2000); and W. H. Miller, et al., xe2x80x9cIdentification and in vivo efficacy of small-molecule antagonists of integrin xcex1vxcex23 (the vitronectin receptor),xe2x80x9d Drug Discovery Today, 5: 397-408 (2000).
However, there still remains a need for small-molecule, non-peptidic selective xcex1v integrin receptor antagonists that display improved potency, pharmacodynamic, and pharmacokinetic properties, such as oral bioavailability and duration of action, over already described compounds. Such compounds would provide an enhancement in the treatment, prevention, or suppression of various pathologies enumerated above that are mediated by xcex1v integrin receptor binding and cell adhesion and activation.
In U.S. Pat. No. 6,017,926 (Jan. 25, 2000) and WO 99/31099 (published 24 Jun. 1999), we disclosed a series of imidazolidinone derivatives which are potent xcex1vxcex23 integrin receptor antagonists. In the present invention, we describe novel imidazolidinone derivatives which are substituted at the N-terminus with novel optionally substituted heterocycles and at C-3 with an optionally substituted aryl group. The compounds of the present invention exhibit improved in vivo pharmacokinetic and/or pharmacodynamic properties over the prior art compounds.
It is therefore an object of the present invention to provide novel imidazolidinone derivatives which are useful as xcex1v integrin receptor antagonists.
It is another object of the present invention to provide novel imidazolidinone derivatives which are useful as xcex1vxcex23 receptor antagonists.
It is another object of the present invention to provide novel imidazolidinone derivatives which are useful as xcex1vxcex25 receptor antagonists.
It is another object of the present invention to provide novel imidazolidinone derivatives which are useful as dual xcex1vxcex23/xcex1vxcex25 receptor antagonists.
It is another object of the present invention to provide pharmaceutical compositions comprising xcex1v integrin receptor antagonists.
It is another object of the present invention to provide methods for making the pharmaceutical compositions of the present invention.
It is another object of the present invention to provide methods for eliciting an xcex1v integrin receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
It is another object of the present invention to provide compounds and pharmaceutical compositions useful for inhibiting bone resorption, restenosis, atherosclerosis, inflammatory arthritis, diabetic retinopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth.
It is another object of the present invention to provide compounds and pharmaceutical compositions useful for treating osteoporosis.
It is another object of the present invention to provide methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammatory arthritis, diabetic retinopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth.
It is another object of the present invention to provide methods for treating osteoporosis.
These and other objects will become readily apparent from the detailed description which follows.
The present invention relates to novel imidazolidinone derivatives represented by structural formula (I), or a pharmaceutically acceptable salt thereof, which are useful as xcex1v integrin receptor antagonists. 
The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
The present invention also relates to methods for making the pharmaceutical compositions of the present invention.
The present invention also relates to methods for eliciting an xcex1v integrin receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammatory arthritis, diabetic retinopathy, macular degeneration, angiogenesis, cancer, and metastatic tumor growth by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for treating osteoporosis by administering the compounds and pharmaceutical compositions of the present invention.
The present invention relates to imidazolidinone derivatives useful as xcex1v integrin receptor antagonists. Representative compounds of the present invention are described by the following structural formula (I): 
or a pharmaceutically acceptable salt thereof, wherein
X is selected from the group consisting of 
each R1 is independently hydrogen or C1-3 alkyl and each non-aromatic ring carbon atom is unsubstituted or independently substituted with one or two R2 substituents and each aromatic ring carbon atom is unsubstituted or independently substituted with one R2 substituent selected from the group consisting of
C1-8 alkyl, C3-8 cycloalkyl,
C3-8 cycloheteroalkyl, C3-8 cycloalkyl-C1-6 alkyl,
C3-8 cycloheteroalkyl-C1-6 alkyl, aryl, aryl-C1-6 alkyl,
amino-C1-6 alkyl, C1-3 acylamino, C1-3 acylamino-C1-6 alkyl,
amino, (C1-6 alkyl)1-2 amino, C3-6 cycloalkyl-C0-2 amino,
(C1-6 alkyl)1-2 amino-C1-6 alkyl, C1-6 alkoxy, C1-4 alkoxy-C1-6 alkyl,
hydroxycarbonyl, hydroxycarbonyl-C1-6 alkyl, C1-3 alkoxycarbonyl,
C1-3 alkoxycarbonyl-C1-6 alkyl, hydroxy, hydroxy-C1-6 alkyl,
nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy,
C1-8 alkyl-S(O)0-2, (C1-8 alkyl)0-2 aminocarbonyl,
C1-8 alkyloxycarbonylamino, (C1-8 alkyl)1-2 aminocarbonyloxy,
(aryl)1-2 amino, aryl-C1-3 alkylsulfonylamino, and C1-8 alkylsulfonylamino;
or two R2 substituents, when on the same non-aromatic carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; or two R2 substituents, together with the carbon atom to which they are attached, join to form a 3- to 6-membered saturated spiro-carbocyclic ring;
R4 is aryl wherein the aryl group is selected from the group consisting of
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) pyrrolyl,
(7) oxazolyl,
(8) thiazolyl,
(9) imidazolyl,
(10) pyrazolyl,
(11) isoxazolyl,
(12) isothiazolyl,
(13) pyrimidinyl,
(14) pyrazinyl,
(15) pyridazinyl,
(16) quinolyl,
(17) isoquinolyl,
(18) benzimidazolyl,
(19) benzofuryl,
(20) benzothienyl,
(21) indolyl,
(22) benzthiazolyl,
(23) benzoxazolyl,
(24) dihydrobenzofuryl,
(25) benzo(1,3)dioxolanyl, and
(26) benzo(1,4)dioxanyl;
and mono, di, and tri-substituted aryl wherein the substituents are independently hydrogen, hydroxy, hydroxy-C1-6 alkyl, halogen, C1-8 alkyl, C3-8 cycloalkyl, aryl, aryl C1-3 alkyl, amino, amino C1-6 alkyl, C1-3 acylamino, C1-3 acylamino-C1-6 alkyl, C1-6 alkylamino, di(C1-6)alkylamino, C1-6 alkylamino-C1-6 alkyl, di(C1-6)alkylamino-C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkoxy-C1l6 alkyl, hydroxycarbonyl, hydroxycarbonyl-C16 alkyl, C1-5 alkoxycarbonyl, C1-3 alkoxycarbonyl-C1-6 alkyl, C1-5 alkylcarbonyloxy, cyano, trifluoromethyl, 1,1,1-trifluoroethyl, trifluoromethoxy, trifluoroethoxy, or nitro; or two adjacent substituents together with the carbon atoms to which they are attached join to form a five- or six-membered saturated or unsaturated ring containing 1 or 2 heteroatoms selected from the group consisting of N, O, and S, whose ring carbon atoms may be substituted with oxo or C1-3 alkyl; and
R3 is hydrogen or C1-3 alkyl.
In one embodiment of the present invention, X is selected from the group consisting of: 
In a second embodiment of the present invention, R4 is mono- or di-substituted
phenyl,
pyridyl,
quinolyl,
pyrimidinyl,
pyrazinyl,
pyrazolyl, or
dihydrobenzofuryl;
wherein the substituents are independently hydrogen, hydroxy, hydroxy-C1-6 alkyl, halogen, C1-8 alkyl, C3-8 cycloalkyl, aryl, aryl C1-3 alkyl, amino, amino-C1-6 alkyl, C1-3 acylamino, C1-3 acylamino-C1-6 alkyl, C1-6 alkylamino, di(C1-6)alkylamino, C1-6 alkylamino C1-6 alkyl, di(C1-6)alkylamino-C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkoxy-C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl-C1-6 alkyl, C1-5 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, C1-5 alkylcarbonyloxy, cyano, trifluoromethyl, 1,1,1-trifluoroethyl, trifluoromethoxy, trifluoroethoxy, or nitro; or two adjacent substituents together with the carbon atoms to which they are attached join to form a five- or six-membered saturated or unsaturated ring containing 1 or 2 heteroatoms selected from the group consisting of N, O, and S, whose ring carbon atoms may be substituted with oxo or C1-3 alkyl.
In a class of this second embodiment of the present invention, R4 is mono- or di-substituted
quinolyl,
pyridyl, or
pyrimidinyl;
wherein the substituents are independently hydrogen, halogen, phenyl, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, amino, C1-3 alkylamino, di(C1-3) alkylamino, hydroxy, cyano, trifluoromethyl, 1,1,1-trifluoroethyl, trifluoromethoxy, or trifluoroethoxy.
In a third embodiment of the present invention, R2 is selected from the group consisting of
hydrogen,
C1-4 alkylamino,
C3-6 cycloalkyl-C0-2 alkylamino
cyano,
C1-4 alkyl,
cyclopropyl,
aryl C1-3 alkyl,
C1-4 acylamino,
C1-4 alkoxy,
C1-4 alkylthio,
aminocarbonyl,
(C1-6 alkyl)1-2 aminocarbonyl,
C1-4 alkoxycarbonyl,
trifluoromethyl, and
trifluoromethoxy.
In a class of this third embodiment of the present invention, R2 is selected from the group consisting of
hydrogen,
C1-3 alkylamino,
C3-6 cycloalkylmethylamino,
C1-4 alkyl,
cyclopropyl,
trifluoromethyl, and
trifluoromethoxy.
Illustrative but nonlimiting examples of compounds of the present invention that are useful as xcex1v integrin receptor antagonists are the following:
3-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3(R)-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3 (S)-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3-(3-{3-[6-(Cyclopropylmethyl-amino)-pyridin-2-yl]-propyl }-2-oxo-imidazolidin-1-yl)-3-(6-methoxy-pyridin-3-yl)-propionic acid;
3-(3-{3-[6-(Cyclopropylmethyl-amino)-pyridin-2-yl]-propyl }-2-oxo-imidazolidin-1-yl)-3(R)-(6-methoxy-pyridin-3-yl)-propionic acid;
3-(3-{3-[6-(Cyclopropylmethyl-amino)-pyridin-2-yl]-propyl }-2-oxo-imidazolidin-1-yl)-3(S)-(6-methoxy-pyridin-3-yl)-propionic acid;
3-(6-Methoxy-pyridin-3-yl)-3-1 2-oxo-3-[3-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-propyl]-imidazolidin-1-yl}-propionic acid;
3(R)-(6-Methoxy-pyridin-3-yl)-3-{2-oxo-3-[3-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-propyl]-imidazolidin-1-yl }-propionic acid;
3(S)-(6-Methoxy-pyridin-3-yl)-3-{2-oxo-3-[3-(6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-propyl]-imidazolidin-1-yl }-propionic acid;
3-(6-Ethoxypyridin-3-yl)-3-{2-oxo-3-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3(R)-(6-Ethoxypyridin-3-yl)-3-{2-oxo-3-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3(S)-(6-Ethoxypyridin-3-yl)-3-{2-oxo-3-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl }-propionic acid;
3-(6-Ethoxy-pyridin-3-yl)-3-{2-oxo-3-[3-(4-methyl-1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propyl]imidazolidin-1-yl]-propionic acid;
3(R)-(6-Ethoxy-pyridin-3-yl)-3-{2-oxo-3-[3-(4-methyl-1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3(S)-(6-Ethoxy-pyridin-3-yl)-3-{2-oxo-3-[3-(4-methyl-1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3-(dihydrobenzofuran-6-yl)-3-{2-oxo-3-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3(R)-(dihydrobenzofuran-6-yl)-3-{2-oxo-3-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3(S)-(dihydrobenzofuran-6-yl)-3-{2-oxo-3-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-imidazolidin-1-yl}-propionic acid;
3-(dihydrobenzofuran-6-yl)-3-{2-oxo-3-[3-(4-amino-2-ethylaminopyriidin-6-yl)-propyl]-imidazolidin-1-yl}-propionic acid;
3(R)-(dihydrobenzofuran-6-yl)-3-{2-oxo-3-[3-(4-amino-2-ethylaminopyriidin-6-yl)-propyl]-imidazolidin-1-yl}-propionic acid;
3(S)-(dihydrobenzofuran-6-yl)-3-{2-oxo-3-[3-(4-amino-2-ethylaminopyrimidin-6-yl)-propyl]-imidazolidin-1-yl}-propionic acid;
3-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-(5,6,7,8-tetrahydro-5,5-ethyleno-[1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl-propionic acid;
3(R)-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-(5,6,7,8-tetrahydro-5,5-ethyleno-[1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl-propionic acid;
3(S)-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-(5,6,7,8-tetrahydro-5,5-ethyleno-[1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl-propionic acid; and
3(S)-(6-Methoxy-pyridin-3-yl)-3-2-oxo-3-(7-methyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl}-propionic acid;
or a pharmaceutically acceptable salt thereof.
In certain embodiments of the present invention, the compounds correspond to the formula (II) with the designated stereochemistry at the carbon atom where R4 is attached: 
wherein the substituents X, R1, R2, R3, and R4 are as described above.
For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Salts of basic compounds encompassed within the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
The compounds of the present invention can have chiral centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers, with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers or diastereomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed within the compounds of the present invention.
Compounds of the present invention may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example, by the use of an optically active acid as a resolving agent, or by BPLC using a chiral stationary phase. Alternatively, any enantiomer of a compound of the present invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugs,xe2x80x9d ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
The term xe2x80x9cxcex1v integrin receptor antagonist,xe2x80x9d as used herein, refers to a compound which binds to and antagonizes either the xcex1vxcex23 receptor or the xcex1vxcex25 receptor, or a compound which binds to and antagonizes a combination of these receptors (for example, a dual xcex1vxcex23/xcex1vxcex25 receptor antagonist).
The term xe2x80x9cbone resorption,xe2x80x9d as used herein, refers to the process by which osteoclasts degrade bone.
The term xe2x80x9calkylxe2x80x9d shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
The term xe2x80x9calkenylxe2x80x9d shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.
The term xe2x80x9calkynylxe2x80x9d shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range.
The term xe2x80x9ccycloalkylxe2x80x9d shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
The term xe2x80x9ccycloheteroalkyl,xe2x80x9d as used herein, shall mean a 3- to 8-membered fully saturated heterocyclic ring containing one or two heteroatoms chosen from N, O, or S. Examples of cycloheteroalkyl groups include, but are not limited to piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., C1-5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a monocyclic or bicyclic system comprising at least one aromatic ring, wherein the monocylic or bicyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O, or S, and wherein the monocylic or bicylic system is either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, C1-8 alkyl, C3-8 cycloalkyl, aryl, aryl C1-3 alkyl, amino, amino C1-6 alkyl, C1-3 acylamino, C1-3 acylamino C1-6 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-6 alkyl, di(C1-6) alkylamino, di(C1-6) alkylamino-C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C1-5 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, trifluoromethoxy, oxo, or C1-5 alkylcarbonyloxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, indolyl, thienyl, furyl, dihydrobenzofuryl, benzo(1,3)dioxolanyl, benzo(1,4)dioxanyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl, which are either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, C1-8 alkyl, C3-8 cycloalkyl, aryl, aryl C1-3 alkyl, amino, amino C1-6 alkyl, C1-3 acylamino, C1-3 acylamino C1-6 alkyl, C1-6 alkylamino, C1-6 alkylamino C1-6 alkyl, di(C1-6) alkylamino, di(C1-6) alkylamino-C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C1-5 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano, trifluoromethyl, trifluoromethoxy, oxo, or C1-5 alkylcarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, di-, or tri- substituted with one to three of the above-named substituents; more preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the above-named substituents.
Whenever the term xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d or either of their prefix roots appears in a name of a substituent (e.g., aryl C0-8 alkyl), it shall be interpreted as including those limitations given above for xe2x80x9calkylxe2x80x9d and xe2x80x9caryl.xe2x80x9d Designated numbers of carbon atoms (e.g., C1-8) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
The terms xe2x80x9carylalkylxe2x80x9d and xe2x80x9calkylarylxe2x80x9d include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.
In the compounds of the present invention, two R2 substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group.
The term xe2x80x9chalogenxe2x80x9d shall include iodine, bromine, chlorine, and fluorine.
The term xe2x80x9coxyxe2x80x9d means an oxygen (O) atom. The term xe2x80x9cthioxe2x80x9d means a sulfur (S) atom. The term xe2x80x9coxoxe2x80x9d means xe2x80x9cxe2x95x90Oxe2x80x9d. The term xe2x80x9ccarbonylxe2x80x9d means xe2x80x9cCxe2x95x90O.xe2x80x9d
The term xe2x80x9csubstitutedxe2x80x9d shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to 
In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. X, R1, R2, R3, and R4 are to be chosen in conformity with well-known principles of chemical structure connectivity.
Representative compounds of the present invention typically display submicromolar affinity for the xcex1v integrin receptors, particularly the xcex1vxcex23 and/or xcex1vxcex25 receptors. Compounds of this invention are therefore useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy. Pharmacologically effective amounts of the compounds, including pharmaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.
The compounds of the present invention are administered in dosages effective to antagonize the xcex1vxcex23 receptor where such treatment is needed, as, for example, in the prevention or treatment of osteoporosis.
Illustrating the invention is the method wherein the xcex1v integrin receptor antagonizing effect is an xcex1vxcex23 antagonizing effect. More particularly, the xcex1vxcex23 antagonizing effect is selected from inhibition of: bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, inflammatory arthritis, viral disease, cancer, or metastatic tumor growth. In one embodiment of the method, the xcex1vxcex23 antagonizing effect is the inhibition of bone resorption.
Another example of the invention is the method wherein the xcex1v integrin receptor antagonizing effect is an xcex1vxcex25 antagonizing effect. More specifically, the xcex1vxcex25 antagonizing effect is selected from inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, cancer, or metastatic tumor growth.
Further illustrating the invention is the method wherein the xcex1v integrin receptor antagonizing effect is a dual xcex1vxcex23/xcex1vxcex25 antagonizing effect. More particularly, the dual xcex1vxcex23/xcex1vxcex25 antagonizing effect is selected from inhibition of: bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, cancer, or metastatic tumor growth.
More particularly illustrating the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
Further illustrating the invention is a method of treating and/or preventing a condition mediated by antagonism of an xcex1v integrin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds described above. Preferably, the condition is selected from bone resorption, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, cancer, tumor growth, and metastasis. More preferably, the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis.
More specifically exemplifying the invention is a method of eliciting an xcex1v integrin antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. Preferably, the xcex1v integrin antagonizing effect is an xcex1vxcex23 antagonizing effect; more specifically, the xcex1vxcex23 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of atherosclerosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of inflammation, or inhibition of cancer or metastatic tumor growth. Most preferably, the xcex1vxcex23 antagonizing effect is inhibition of bone resorption. Alternatively, the integrin antagonizing effect is an xcex1vxcex25 antagonizing effect or a dual xcex1vxcex23/xcex1vxcex25 antagonizing effect. Examples of xcex1vxcex25 antagonizing effects are inhibition of restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, cancer, or metastatic tumor growth.
Additional examples of the invention are methods of inhibiting bone resorption and of treating and/or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.
Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget""s disease, immobilization-induced osteopenia, and glucocorticoid treatment in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.
More particularly exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of bone resorption, cancer, metastatic tumor growth, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammatory arthritis, and/or angiogenesis.
Also exemplifying the invention are compositions further comprising an active ingredient selected from the group consisting of
a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof,
b) an estrogen receptor modulator,
c) an androgen receptor modulator,
d) a cytotoxic/antiproliferative agent,
e) a matrix metalloproteinase inhibitor,
f) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors,
g) an inhibitor of VEGF,
h) an antibody to a growth factor or to a growth factor receptor,
i) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1,
j) a cathepsin K inhibitor,
k a growth hormone secretagogue,
l) an inhibitor of osteoclast proton ATPase,
m) an inhibitor of urokinase plasminogen activator (u-PA),
n) a tumor-specific antibody-interleukin-2 fusion protein,
o) an inhibitor of HMG-CoA reductase,
p) a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; and
q) human parathyroid hormone (hPTH) or human parathyroid hormone fragment (1-34);
and mixtures thereof.
(See, B. Millauer et al., xe2x80x9cDominant-Negative Inhibition of Flk-1 Suppresses the Growth of Many Tumor Types in Vivoxe2x80x9d, Cancer Research, 56, 1615-1620 (1996), which is incorporated by reference herein in its entirety).
Preferably, the active ingredient is selected from the group consisting of:
a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof,
b) an estrogen receptor modulator,
c) an androgen receptor modulator,
d) an inhibitor of osteoclast proton ATPase,
e) an inhibitor of HMG-CoA reductase, and
f) a cathepsin K inhibitor; and mixtures thereof.
Nonlimiting examples of such bisphosphonates include alendronate, cimadronate, clodronate, etidronate, ibandronate, pamidronate, pimidronate, risedronate, tiludronate, and zolendronate, and pharmaceutically acceptable salts and esters thereof. A particularly preferred bisphosphonate is alendronate, especially alendronate monosodium trihydrate.
Nonlimiting examples of estrogen receptor modulators include estrogen, progesterin, estradiol, droloxifene, raloxifene, and tamoxifene.
Nonlimiting examples of cytotoxic/antiproliferative agents are taxol, vincristine, vinblastine, and doxorubicin.
Cathepsin K, formerly known as cathepsin O2, is a cysteine protease and is described in PCT International Application Publication No. WO 96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3, 1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which are incorporated by reference herein in their entirety. Cysteine proteases, specifically cathepsins, are linked to a number of disease conditions, such as tumor metastasis, inflammation, arthritis, and bone remodeling. At acidic pH""s, cathepsins can degrade type-I collagen. Cathepsin protease inhibitors can inhibit osteoclastic bone resorption by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone resorption diseases, such as osteoporosis.
Members of the class of HMG-CoA reductase inhibitors, known as the xe2x80x9cstatins,xe2x80x9d have been found to trigger the growth of new bone, replacing bone mass lost as a result of osteoporosis (see The Wall Street Journal, Friday, Dec. 3, 1999, page B1). Therefore, the statins hold promise for the treatment of bone resorption. Nonlimiting examples of statins are lovastatin, simvastatin, atorvastatin, pravastatin, fluvastatin, cerivastatin, and rosuvastatin. Evidence for crucial role of the urokinase-urokinase receptor (u-PA-u-PAR) in angiogenesis, tumor invasion, inflammation, and matrix remodeling during wound healing and development has been presented [see Y. Koshelnick et al., xe2x80x9cMechanisms of signaling through Urokinase Receptor and the Cellular Response,xe2x80x9d Thrombosis and Haemostasis 82: 305-311 (1999) and F. Blasi, xe2x80x9cProteolysis, Cell Adhesion, Chemotaxis, and Invasiveness Are Regulated by the u-PA-u-PAR-PAI-1 System,xe2x80x9d Thrombosis and Haemostasis 82: 298-304 (1999)]. Thus, specific antagonists of the binding of u-PA to u-PAR have been found to inhibit cell-surface plasminogen activation, tumor growth, and angiogenesis in both in vitro and in vivo models.
H. N. Lode and coworkers in PNAS USA 96: 1591-1596 (1999) have observed synergistic effects between an antiangiogenic xcex1v integrin antagonist and a tumor-specific antibody-cytokine (interleukin-2) fusion protein in the eradication of spontaneous tumor metastases. Their results suggested this combination as having potential for the treatment of cancer and metastatic tumor growth.
The proton ATPase which is found on the apical membrane of the osteoclast has been reported to play a significant role in the bone resorption process. Therefore, this proton pump represents an attractive target for the design of inhibitors of bone resorption which are potentially useful for the treatment and prevention of osteoporosis and related metabolic diseases (see C. Farina et al., xe2x80x9cSelective inhibitors of the osteoclast vacuolar proton ATPase as novel bone antiresorptive agents,xe2x80x9d DDT, 4:163-172 (1999)).
Evidence has been presented that androgenic steroids play a physiological role in the development of bone mass in men and women and that androgens act directly on bone. Androgen receptors have been demonstrated in human osteoblast-like cell lines and androgens have been shown to directly stimulate bone cell proliferation and differentiation. For a discussion, reference is made to S. R. Davis, xe2x80x9cThe therapeutic use of androgens in women,xe2x80x9d J. Steroid Biochem. Mol. Biol., 69: 177-184 (1999) and K. A. Hansen and S. P. T. Tho, xe2x80x9cAndrogens and Bone Health,xe2x80x9d Seminars in Reproductive Endocrinology,xe2x80x9d 16: 129-134 (1998). Thus, androgen receptor modulators may have utility in the treatment and prevention of bone loss in women.
The angiogenic factor VEGF has been shown to stimulate the bone-resorbing activity of isolated mature rabbit osteoclasts via binding to its receptors on osteoclasts (see M. Nakagawa et al., xe2x80x9cVascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts,xe2x80x9d FEBS Letters, 473: 161-164 (2000)). Therefore, the development of antagonists of VEGF binding to osteoclast receptors, such as KDR/Flk-1 and Flt-1, may provide yet a further approach to the treatment or prevention of bone resorption.
Activators of the peroxisome proliferator-activated receptor-xcex3(PPARxcex3), such as the thiazolidinediones (TZD""s), inhibit osteoclast-like cell formation and bone resorption in vitro. Results reported by R. Okazaki et al. in Endocrinology, 140: 5060-5065 (1999) point to a local mechanism on bone marrow cells as well as a systemic one on glucose metabolism. Nonlimiting examples of PPARxcex3 activators include troglitazone, pioglitazone, rosiglitazone, and BRL 49653.
Parathyroid hormone (PTH) is the major circulating hormone, secreted by the parathyroid gland, that functions to maintain calcium homeostasis. PTH has been shown to increase the activity of osteoblasts, the cells that form bone, and to increase bone size as well as density. The PTH fragment hPTH(1-34) has been demonstrated to have anabolic effects in osteoporotic humans. A large clinical trial of the effect of hPTH(1-34) on postmenopausal osteoporotic women reported xe2x89xa765% reduction in spine fractures and a 54% reduction in nonvertebral fractures after a median of 22 months of treatment (see J. M. Hock, xe2x80x9cxe2x80x9dDiscrimination among osteoblasts? Parathyroid Hormone Analog May Reveal Site-Specific Differences in Mice,xe2x80x9d Bone, 27: 467-469 (2000) and references cited therein). Hence, PTH and fragments thereof, such as hPTH(1-34) (LY333334), are other potential agents for the treatment of osteoporosis.
The present invention is also directed to combinations of the compounds of the present invention with one or more agents useful in the prevention or treatment of osteoporosis. For example, the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents such as an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, a cathepsin K inhibitor, an HMG-CoA reductase inhibitor, a PPARxcex3 activator, or an inhibitor of the osteoclast proton ATPase.
Additional illustrations of the invention are methods of treating tumor growth or metastasis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound described above and one or more agents known to be cytotoxic/antiproliferative. Also, the compounds of the present invention can be administered in combination with radiation therapy for treating cancer and metastatic tumor growth.
In addition, the integrin xcex1vxcex23 antagonist compounds of the present invention may be effectively administered in combination with a growth hormone secretagogue in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases. These diseases include conditions which can benefit from a reduction in bone resorption. A reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result in bone augmentation. A reduction in bone resorption can alleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions. These diseases include: osteoporosis (including estrogen deficiency, immobilization, glucocorticoid-induced and senile), osteodystrophy, Paget""s disease, myositis ossificans, Bechterew""s disease, malignant hypercalcemia, metastatic bone disease, periodontal disease, cholelithiasis, nephrolithiasis, urolithiasis, urinary calculus, hardening of the arteries (sclerosis), arthritis, bursitis, neuritis and tetany. Increased bone resorption can be accompanied by pathologically high calcium and phosphate concentrations in the plasma, which would be alleviated by this treatment. Similarly, the present invention would be useful in increasing bone mass in patients with growth hormone deficiency. Thus, preferred combinations are simultaneous or alternating treatments of an xcex1vxcex23 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component comprising an organic bisphosphonate, preferably alendronate monosodium trihydrate.
In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment, and the term xe2x80x9cadministeringxe2x80x9d is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating integrin-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating osteoporosis.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, topical (e.g., ocular eyedrop), subcutaneous, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an xcex1vxcex23 antagonist.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as xe2x80x98carrierxe2x80x99 materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
In the Schemes and Examples below, various reagent symbols and abbreviations have the following meanings:
The novel compounds of the present invention can be prepared according to the procedures of the following reaction Schemes and Examples, or modifications thereof, using readily available starting materials, reagents, and, where appropriate, conventional synthetic procedures. In these procedures, it is also possible to make use of variants which are themselves known to those of ordinary skill in the organic synthetic arts, but are not mentioned in greater detail.
The following Examples are illustrative of the more preferred compounds of the present invention. They are not, however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. Unless stated otherwise, all operations were carried out at room or ambient temperature, and all temperatures are degrees Celsius. 